title: Investigating interventions in Alzheimer's disease with computer simulation models.
abstract: Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Carole J
authors.initials: CJ
authors.lastname: Proctor
authors.forename: Delphine
authors.initials: D
authors.lastname: Boche
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Gray
authors.forename: James A R
authors.initials: JA
authors.lastname: Nicoll
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D003198:Computer Simulation / Q000639:trends; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D007114:Immunization; D007167:Immunotherapy / Q000379:methods*; D008954:Models, Biological; D049490:Systems Biology; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D016875:tau Proteins